Ignite Creation Date:
2024-05-05 @ 11:28 AM
Last Modification Date:
2024-10-26 @ 9:08 AM
Study NCT ID:
NCT00048646
Status:
COMPLETED
Last Update Posted:
2014-09-19
First Post:
2002-11-04
Brief Title:
Progesterone Treatment of Blunt Traumatic Brain Injury
Sponsor:
David Wright
Organization:
Emory University
Study Overview
Official Title:
ProTECT Single Center Phase II Pilot Double Blind 41 Randomized Placebo Controlled Clinical Trial for Progesterone Treatment of Moderate and Severe Blunt TBI
Status:
COMPLETED
Status Verified Date:
2014-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to determine if progesterone treatment safely reduces brain swelling and damage after injury
Detailed Description:
Title Progesterone Treatment of Blunt Traumatic Brain Injury Principal Investigators Arthur Kellermann MD MPH Institution Emory University Biostatistician Vicki Hertzberg PhD Institution Emory University Project phase or primary methodology Phase II pilot double blind 41 randomized controlled clinical trial Target disease Blunt traumatic brain injury Intervention Intravenous progesterone infused over three days Number of patients to be enrolled 100 Number of clinical centers One Grady Memorial Hospital Primary Hypothesis Dose Intravenous infusion of progesterone at a dose of 05 mgkghr produces a steady state of 450 - 100 nmolL in male and female subjects
Safety Compared to study subjects who receive placebo subjects who receive IV progesterone do not have an increased risk of mortality or an increased incidence of adverse effects
Efficacy Administering IV progesterone shortly following TBI produces any or all of the following effects including
Reduction of the intracranial pressure therapeutic intensity level ICP-TIL
Decreased duration of coma
Decreased inpatient mortality
Improved neurological outcome one month post-injury
Secondary Hypotheses Benefit The benefits of IV progesterone for TBI are evident across a range of clinically relevant treatment subgroups regardless of
Time from injury to drug administration ie 2 hrs vs 2-4 hrs vs 4-6 hrs
Victim gender
Presence or absence of severe extracranial trauma
Presence or absence of premorbid confounders of outcome eg alcohol intoxication alcoholism stroke etc
Incidence or lack of confounding neurological insults eg hypoxemia hypotension
Severity of the traumatic brain injury - moderate index GCS 9-12 versus severe index GCS 4-8
Severity of non-brain injuries AIS ISS scores
Description of methodology and design Double blind randomized controlled clinical trial Block randomization will be used to insure that moderate and severely injured patients of both genders and races black and nonblack have an equal chance of allocation to either treatment group
Patient selection criteria Age 18 blunt traumatic brain injury moderate to severe brain injury iGCS 4-12 arrival 11 hours after Injury
Description of pre-randomization procedures or process Potential study subjects will be identified by Emergency Medical Service EMS personnel and Emergency Medicine attending physicians and residents in the ECC of GMH EMS ambulance personnel will notify ECC personnel that they are bringing a blunt trauma patient with a Glasgow Coma Score iGCS of 12 or less On arrival the attending emergency physician on duty will conduct a primary and secondary trauma survey and note the patients post initial resuscitation or i GCS If the patient has a iGCS of 4 - 12 and meets criteria for presumptive eligibility the ECC attending will page the investigator on-call IOC and ask Hospital Social Services to initiate aggressive efforts to contact the patients family To insure prompt administration of progesteroneplacebo a door to needle time of 2 hours has been established as our performance goal To meet this deadline a member of the research team will immediately respond to the ECC and determine if the patient meets the inclusion and exclusion criteria Time from injury will be established as clearly as possible from the EMS report police report or witness interview Block randomization will be used to insure that moderate and severely injured patients of both genders and races black and nonblack have an equal chance of allocation to either treatment group To accomplish this goal the GMH pharmacy will be given block sets of randomly ordered packets with sequential study numbers for subjects with moderate TBI presenting GCS 9-12 and severe TBI presenting GCS 4-8 Inside each packet will be instructions to prepare an infusion of progesterone or a comparable volume of placebo When the pharmacist receives a copy of the randomization request heshe will open the next packet in sequence based on the patients severity of brain injury moderate versus severe gender and race Following treatment group assignment the pharmacist will record the patients name medical record number dose and time the medication was prepared in a confidential log for use by the Safety Committee
Precise treatment dose description for protocol Our goal is to initiate treatment within 2 hours of injury as documented from an EMS report police report or witness interview We will accept patients up to 11 hours post-injury We will attempt to achieve serum levels of progesterone in human subjects that are similar to those normally observed in the third trimester of pregnancy ie 450 - 100 nmolL
To determine the infusion rate needed to achieve a SSSPC of progesterone of 450 - 100nmolL we will conduct a dose-escalation study The first 12 subjects randomized to progesterone will receive a loading dose of 0714 mgkg over 60 minutes followed by a continuous infusion of 050 mgkghr for three days Because study personnel will be blinded to group assignment an unblinded pharmacologist will analyze the SSSPC data from these 12 patients If the target concentration of 450 - 100nmolL is not achieved in 90 of these subjects the infusion rate will be modified and applied to the next ten subjects randomized to progesterone therapy This will be performed a third time if necessary If pharmacokinetic variability precludes the achievement of the target concentration in 90 of subjects using a fixed infusion we will adopt an individualized dosing strategy based on real-time serum concentration data If this is required adjustments will be made to the placebo infusions as well to maintain blinding of the study investigators The total dose given to any patient over the three day dosing period should not exceed 75 grams
Plan for Follow-up
The GOS DRS and GOAT will be assessed at one month post-injury At the time of hospital discharge each patients disposition will be noted morgue nursing home rehabilitation facility another acute care hospital patients home relatives home so plans can be made for a follow-up exam one month post-injury Subjects who are still hospitalized at GMH an inpatient rehabilitation facility a skilled nursing home or an acute care hospital other than GMH one month post-injury will be tested on site We will visit patients who are homebound at the time of follow-up All other subjects will be asked to come to a study clinic at GMH for testing Patients who are too severely impaired to test at one month post-injury will be classified as not testable This category will be considered a surrogate marker for a poor outcome We will utilize reliability codes to record all possible reasons for the non-administration of a particular measure such as physical impairment eg hemiparesis cognitive impairment eg did not understand instructions or intoxication
During the follow-up visit the study subject or a proxy respondent will be asked questions about their physical and mental health any medical complications eg seizure disorder and headaches their functional status their occupational status their level of sexual function and their current living situation Information on other variables that influence outcome such as access to rehabilitation services will be collected as well To encourage participation subjects will be reimbursed 25 for the follow-up visit plus additional money for travel-related expenses
Extent and type of blindingmasking Hospital pharmacy personnel will know each patients group assignment but this information will be withheld from the patient the study team and the clinical team responsible for the patients care Both study drug and placebo will be suspended in a lipid base and will be indistinguishable by color or injection characteristics
Endpoints and outcomes Four measures will be used to monitor each patients clinical response to treatment The first three will be tracked daily by our study nurses The fourth will be assessed one month post-injury These four measures are
1 Reduction in ICP reflected by a decline in the patients therapeutic intensity level ICP-TIL a measure of the intensity of treatment needed to reduce increased intracranial pressure
2 Duration of coma ie total hours from injury to awakening
3 Death prior to hospital discharge
4 Neurological outcome at one month post -injury as measured by the Glasgow Outcome Scale GOS the Disability Rating Scale DRS and the Galveston Orientation and Amnesia Test GOAT
Statistical design and sample size calculations Our data analysis strategy is designed to accomplish our three primary and one secondary goals 1 achieve and maintain a predetermined steady state concentration of progesterone in 90 of our study patients 2 confirm the safety of the study drug 3 test the hypothesis that administration of progesterone within 6 hours of TBI improves clinical and neurological outcomes and the secondary determine if the benefit of IV progesterone is equally evident across a range of clinically relevant treatment subgroups In the process of achieving these goals we will quantify our ability to identify and enroll TBI patients administer the study drug within strict time restraints and adhere to the study protocol
To assess the efficacy of progesterone for treatment of TBI we will employ a systematic statistical analysis strategy Our first analytic step will be to compile descriptive statistics eg mean median standard deviation range proportion of patient demographics This activity while not directly addressing any of the study hypotheses will serve to describe the central tendencies and variability of the outcome variables and covariables
The second step will be to compare treatment groups with respect to suspected important covariates specifically patient age gender cause and type of brain injury presence or absence of intracranial mass lesions presenceabsence of extracranial trauma presenceabsence of premorbid confounders eg alcohol intoxication alcoholism stroke etc presenceabsence of confounding neurological insults eg hypoxemia hypotension severity of TBI and time to initial drug administration This will assess the balance achieved through randomization The third step will be to analyze the data according to our specific aims
To estimate the sample size needed to establish efficacy we needed to specify the effect size to be detected by our outcome measures We do not have any human data to definitively establish the effect size expected as a result of treatment Based on animal models we conservatively posit that progesterone will improve neurological outcome ie dichotimized GOS DRS GOAT at one month post-injury by 25 We expect to enroll 100 subjects at a 41 randomization 80 treated and 20 controls into our pilot study With respect to duration of coma the number of patients that would allow us to achieve 80 power to detect a difference of at least 06 standard deviation between treatment groups at the two-sided 005 significance level was 50 treated and 50 controls For this outcome a difference of 06 standard deviation units translates into a difference of 11 days or 29 based on the findings of Stambrook et al6 However since we have changed our protocol to a 41 randomization we no longer have the power to detect this difference Similarly in the subgroup of patients monitored for differences in the ICP-TIL in the original 11 randomization scheme we would have been able to achieve 80 power to detect a difference of at least 10 standard deviation between treatment groups at the two-sided 005 significance level but with the 41 scheme no longer have the power to detect a difference With respect to mortality our pilot will have insufficient power 50 to definitively detect an effect size equal to 25 reduction in the rate of death Similarly there is insufficient power to detect a good neurological outcome at hospital discharge or at one month post-injury using a dichotomized GOS good or moderate recovery versus severe disability with the expectation of 50 with good outcome in the placebo group based on the findings of Levin et al However this study should allow us to perceive trends in the data as well as determine the range and prevalence of outcomes that we might anticipate for a multi-center study of this therapy This will allow us to refine our future power calculations appropriately
Initially there will be a dose escalation component within the progesterone group but the differences in the level of circulating progesterone between the subgroups will be minimal compared to the control group Hence all progesterone treated patients are assumed to respond similarly to the treatment 2 At the completion of the pilot phase at least 100 patients will be randomized into this study GMHs trauma registry indicates that at least 145 potentially eligible TBI patients age 18 GCS 4-12 blunt mechanism and 11 hours from injury will come to GMH during the study interval Every effort will be made to obtain informed consent from a proxy in order to administer the study drug within the specified time limit 2 hours
Proposed safety and efficacy monitoring boundaries
Data Safety and Monitoring Board DSMB In accordance with standard procedures for NIH sponsored clinical trials the DSMB chair and members have been selected by the NIH-NINDS This committee will be informed of each subjects group assignment A versus B but will be blinded with respect to which group received the study drug
This committee will have three responsibilities 1 monitor identification enrollment and randomization procedures to detect any evidence of bias 2 monitor adverse events to determine if they occur disproportionately in one group and 3 monitor key clinical outcomes to determine if one group does significantly better than the other To assist the DSMB in its work our statistician Vicki Hertzberg will monitor the progress of the study on a monthly basis The DSMB will have no role in the day-to-day conduct of the trial The study statistician will report to the DSMB at quarterly meetings
Safety Monitoring A study nurse andor the research program coordinator will round on subjects daily to track their clinical progress and the occurrence of any serious adverse events SAE or adverse events AE All SAEs will be reported to the IRB DSMB and FDA within 24 hours All other adverse events will be reported to the PI IRB and FDA on a weekly basis Specific events potentially related to the study drug based on prior knowledge of the pharmacology of progesterone combination agents that include progesterone and the Intralipid carrier will be closely monitored by the study team These events include a phlebitis at the injection site b sedation unexplained by administration of other CNS medications c an increase in liver enzymes d unexplained hyperglycemia e hypotension or hypertension not known to be associated with increased intracranial pressure f unexplained fever g thromboembolic disease and h sepsis Baseline metabolic parameters will be determined from the initial blood draw prior to study drug administration Blood sampling will be performed at least once per day during drug administration for monitoring In addition hourly vital sign measurements and other parameters will be obtained from ICU charting forms Patients will be examined daily by team members for any signs of adverse reactions Team members will also review charting laboratory reports and treating physician notes daily In addition all trauma deaths are reviewed by an interdisciplinary Trauma Outcome Review Committee TORC to determine if the death was non-preventable potentially preventable or preventable A member of our study team will attend all of these meetings Ifwhen TORC reviews a death involving a participant in the study their findings will be shared with the DSMB as well as the PI and co-PI The DSMB will closely monitor the incidence of death and other serious adverse events such as sepsis or thromboembolic disease If they have concerns about the incidence of any of these events as linked to the study drug they will immediately report these concerns to the National Institute for Neurological Disorders and Stroke NINDS as well as to the Emory IRB Furthermore all occurrences of death regardless of cause and unexpected serious adverse events will be reported to the Food and Drug Administration FDA
Efficacy To assess the efficacy of the drug on an interim basis there will be a comparison of the study groups with respect to the endpoints mortality duration of coma ICP-TIL and neurological status indicators at one month at the time when 12 24 and 48 patients have been entered into the trial Comparisons at these interim points which exceed a z-score of 2782 associated p-value of 00054 will be considered significant using the OBrien-Fleming procedure
To determine if one treatment group does better than the other the teams study nurses will obtain the following outcome measures 1 ICP-TIL 2 duration of coma 3 in-hospital mortality 4 Glasgow Outcome Score 5 Disability Rating Scale and 6 Galveston Orientation and Amnesia Test The DSMB will monitor these outcomes by treatment group A versus B in order to promptly identify any between-group differences If significant differences are noted the code will be broken and our findings will be immediately reported to the Emory IRB the FDA the NINDS and DSMB
Patient accrual plan
We will enroll the first 100 eligible patients over a two year enrollment period
Ethical and consent considerations
Since our study involves treatment of patients with acute neurological impairment they are not competent to give informed consent We will therefore seek proxy consent from the patients family or next-of-kin or legally authorized representative LAR If an LAR is subsequently located that objects to the study the process will be halted and the patients participation will be terminated Only the IOCs or the study coordinator will be permitted to approach family members to request consent
A written form that complies with the polices and procedures of Emory Universitys IRB has been developed and approved This form includes the following elements title of the protocol the name of the PI study objectives and purpose a detailed description of the procedure and interventions explanation of the responsibilities of the subject and of the family members who act as proxy respondents during follow-up interviews any and all foreseeable risks anticipated benefits available alternatives an explicit statement of confidentiality non-compensation for participation the right to withdraw at any time a signature section and a number to contact the PI or a member of the study team with any questions
Given the sudden unanticipated nature of traumatic brain injury and the potential time delays involved in getting a family member to the hospital we have been authorized by the IRB to obtain proxy consent for participation over the telephone When this is necessary the on-call investigator will contact the family member provide a brief explanation of the situation read the consent form verbatim and request verbal consent over the telephone A third party will listen in to confirm that the family member understands and has provided proxy consent On the signature line of the form the witness will print the name of the consenting proxy write their own name immediately below this name note the time and date of the telephone call and check a box labeled telephone consent
Before recruiting the first patient in this study we will undertake a comprehensive process to notify and consult the target communities that use GMH as their trauma center The Emory University News and Information office has pledged its support On the advice of Emory Healthcare marketing we have allocated 40000 to support marketing and community outreach activity during the first 6 months of the study Lesser amounts have been allocated to keep the community informed in years 2 and 3 An independent interdisciplinary Safety Committee has been created to provide additional monitoring for study safety
In addition to designating a Safety Committee we will convene an independent citizen advisory committee Two influential Atlantans have agreed to co-chair this group One is Rev Gerald Durley Pastor of Providence Missionary Baptist Church one of Atlantas largest African-American congregations Rev Durley is also a key member of Concerned Black Clergy a local activist group The other co-chair is Sandy Teepen a TBI survivor safety advocate and wife of a national newspaper columnist and former editorial page editor for the Atlanta Constitution the largest circulation newspaper in the Southeastern United States
Progesterone has been used for many years to treat a variety of medical conditions Side effects ascribed to its use alone are minimal Minor adverse reactions include temperature elevations of 1 degree Fahrenheit mood changes depression following drug withdrawal vaginal cervical and uterine lining changes irregular vaginal bleeding or amenorrhea hyperventilation mild fluid retention a transient increase in low density lipoprotein LDL a transient decrease in high density lipoprotein HDL interference with lactation during breast feeding nausea abdominal cramping dizziness headaches breast pain and a delay in fertility Most of these effects are associated with prolonged administration of progesterone ie weeks to months They are unlikely to be experienced during short-course administration ie 3 days
Throughout the pilot trial subjects will be monitored for potential side effects of drug therapy ie hyperglycemia hypertension unexplained by increases in ICP unexplained fever local phlebitis thromboembolic disease abnormal vaginal bleeding The Safety Committee will meet quarterly to review group-specific clinical outcomes and side effects If they are concerned that one group is doing significantly better or worse than the other they have the authority to break the code and order premature termination of the trial
Participating pharmaceutical or device manufacturing company None
Proposed sponsor or funding agencies NINDS NIH
Significance of the Research and Impact on Medical Care If the therapeutic benefits observed in animals are replicated in humans administration of intravenous progesterone should produce several benefits including a reduction of intracerebral pressure b decreased duration of coma c decreased mortality and d improved neurological function at one month post-injury If these findings are verified it will represent a major advance in the treatment of traumatic brain injury
Safety Compared to study subjects who receive placebo subjects who receive IV progesterone do not have an increased risk of mortality or an increased incidence of adverse effects
Efficacy Administering IV progesterone shortly following TBI produces any or all of the following effects including
Reduction of the intracranial pressure therapeutic intensity level ICP-TIL
Decreased duration of coma
Decreased inpatient mortality
Improved neurological outcome one month post-injury
Secondary Hypotheses Benefit The benefits of IV progesterone for TBI are evident across a range of clinically relevant treatment subgroups regardless of
Time from injury to drug administration ie 2 hrs vs 2-4 hrs vs 4-6 hrs
Victim gender
Presence or absence of severe extracranial trauma
Presence or absence of premorbid confounders of outcome eg alcohol intoxication alcoholism stroke etc
Incidence or lack of confounding neurological insults eg hypoxemia hypotension
Severity of the traumatic brain injury - moderate index GCS 9-12 versus severe index GCS 4-8
Severity of non-brain injuries AIS ISS scores
Description of methodology and design Double blind randomized controlled clinical trial Block randomization will be used to insure that moderate and severely injured patients of both genders and races black and nonblack have an equal chance of allocation to either treatment group
Patient selection criteria Age 18 blunt traumatic brain injury moderate to severe brain injury iGCS 4-12 arrival 11 hours after Injury
Description of pre-randomization procedures or process Potential study subjects will be identified by Emergency Medical Service EMS personnel and Emergency Medicine attending physicians and residents in the ECC of GMH EMS ambulance personnel will notify ECC personnel that they are bringing a blunt trauma patient with a Glasgow Coma Score iGCS of 12 or less On arrival the attending emergency physician on duty will conduct a primary and secondary trauma survey and note the patients post initial resuscitation or i GCS If the patient has a iGCS of 4 - 12 and meets criteria for presumptive eligibility the ECC attending will page the investigator on-call IOC and ask Hospital Social Services to initiate aggressive efforts to contact the patients family To insure prompt administration of progesteroneplacebo a door to needle time of 2 hours has been established as our performance goal To meet this deadline a member of the research team will immediately respond to the ECC and determine if the patient meets the inclusion and exclusion criteria Time from injury will be established as clearly as possible from the EMS report police report or witness interview Block randomization will be used to insure that moderate and severely injured patients of both genders and races black and nonblack have an equal chance of allocation to either treatment group To accomplish this goal the GMH pharmacy will be given block sets of randomly ordered packets with sequential study numbers for subjects with moderate TBI presenting GCS 9-12 and severe TBI presenting GCS 4-8 Inside each packet will be instructions to prepare an infusion of progesterone or a comparable volume of placebo When the pharmacist receives a copy of the randomization request heshe will open the next packet in sequence based on the patients severity of brain injury moderate versus severe gender and race Following treatment group assignment the pharmacist will record the patients name medical record number dose and time the medication was prepared in a confidential log for use by the Safety Committee
Precise treatment dose description for protocol Our goal is to initiate treatment within 2 hours of injury as documented from an EMS report police report or witness interview We will accept patients up to 11 hours post-injury We will attempt to achieve serum levels of progesterone in human subjects that are similar to those normally observed in the third trimester of pregnancy ie 450 - 100 nmolL
To determine the infusion rate needed to achieve a SSSPC of progesterone of 450 - 100nmolL we will conduct a dose-escalation study The first 12 subjects randomized to progesterone will receive a loading dose of 0714 mgkg over 60 minutes followed by a continuous infusion of 050 mgkghr for three days Because study personnel will be blinded to group assignment an unblinded pharmacologist will analyze the SSSPC data from these 12 patients If the target concentration of 450 - 100nmolL is not achieved in 90 of these subjects the infusion rate will be modified and applied to the next ten subjects randomized to progesterone therapy This will be performed a third time if necessary If pharmacokinetic variability precludes the achievement of the target concentration in 90 of subjects using a fixed infusion we will adopt an individualized dosing strategy based on real-time serum concentration data If this is required adjustments will be made to the placebo infusions as well to maintain blinding of the study investigators The total dose given to any patient over the three day dosing period should not exceed 75 grams
Plan for Follow-up
The GOS DRS and GOAT will be assessed at one month post-injury At the time of hospital discharge each patients disposition will be noted morgue nursing home rehabilitation facility another acute care hospital patients home relatives home so plans can be made for a follow-up exam one month post-injury Subjects who are still hospitalized at GMH an inpatient rehabilitation facility a skilled nursing home or an acute care hospital other than GMH one month post-injury will be tested on site We will visit patients who are homebound at the time of follow-up All other subjects will be asked to come to a study clinic at GMH for testing Patients who are too severely impaired to test at one month post-injury will be classified as not testable This category will be considered a surrogate marker for a poor outcome We will utilize reliability codes to record all possible reasons for the non-administration of a particular measure such as physical impairment eg hemiparesis cognitive impairment eg did not understand instructions or intoxication
During the follow-up visit the study subject or a proxy respondent will be asked questions about their physical and mental health any medical complications eg seizure disorder and headaches their functional status their occupational status their level of sexual function and their current living situation Information on other variables that influence outcome such as access to rehabilitation services will be collected as well To encourage participation subjects will be reimbursed 25 for the follow-up visit plus additional money for travel-related expenses
Extent and type of blindingmasking Hospital pharmacy personnel will know each patients group assignment but this information will be withheld from the patient the study team and the clinical team responsible for the patients care Both study drug and placebo will be suspended in a lipid base and will be indistinguishable by color or injection characteristics
Endpoints and outcomes Four measures will be used to monitor each patients clinical response to treatment The first three will be tracked daily by our study nurses The fourth will be assessed one month post-injury These four measures are
1 Reduction in ICP reflected by a decline in the patients therapeutic intensity level ICP-TIL a measure of the intensity of treatment needed to reduce increased intracranial pressure
2 Duration of coma ie total hours from injury to awakening
3 Death prior to hospital discharge
4 Neurological outcome at one month post -injury as measured by the Glasgow Outcome Scale GOS the Disability Rating Scale DRS and the Galveston Orientation and Amnesia Test GOAT
Statistical design and sample size calculations Our data analysis strategy is designed to accomplish our three primary and one secondary goals 1 achieve and maintain a predetermined steady state concentration of progesterone in 90 of our study patients 2 confirm the safety of the study drug 3 test the hypothesis that administration of progesterone within 6 hours of TBI improves clinical and neurological outcomes and the secondary determine if the benefit of IV progesterone is equally evident across a range of clinically relevant treatment subgroups In the process of achieving these goals we will quantify our ability to identify and enroll TBI patients administer the study drug within strict time restraints and adhere to the study protocol
To assess the efficacy of progesterone for treatment of TBI we will employ a systematic statistical analysis strategy Our first analytic step will be to compile descriptive statistics eg mean median standard deviation range proportion of patient demographics This activity while not directly addressing any of the study hypotheses will serve to describe the central tendencies and variability of the outcome variables and covariables
The second step will be to compare treatment groups with respect to suspected important covariates specifically patient age gender cause and type of brain injury presence or absence of intracranial mass lesions presenceabsence of extracranial trauma presenceabsence of premorbid confounders eg alcohol intoxication alcoholism stroke etc presenceabsence of confounding neurological insults eg hypoxemia hypotension severity of TBI and time to initial drug administration This will assess the balance achieved through randomization The third step will be to analyze the data according to our specific aims
To estimate the sample size needed to establish efficacy we needed to specify the effect size to be detected by our outcome measures We do not have any human data to definitively establish the effect size expected as a result of treatment Based on animal models we conservatively posit that progesterone will improve neurological outcome ie dichotimized GOS DRS GOAT at one month post-injury by 25 We expect to enroll 100 subjects at a 41 randomization 80 treated and 20 controls into our pilot study With respect to duration of coma the number of patients that would allow us to achieve 80 power to detect a difference of at least 06 standard deviation between treatment groups at the two-sided 005 significance level was 50 treated and 50 controls For this outcome a difference of 06 standard deviation units translates into a difference of 11 days or 29 based on the findings of Stambrook et al6 However since we have changed our protocol to a 41 randomization we no longer have the power to detect this difference Similarly in the subgroup of patients monitored for differences in the ICP-TIL in the original 11 randomization scheme we would have been able to achieve 80 power to detect a difference of at least 10 standard deviation between treatment groups at the two-sided 005 significance level but with the 41 scheme no longer have the power to detect a difference With respect to mortality our pilot will have insufficient power 50 to definitively detect an effect size equal to 25 reduction in the rate of death Similarly there is insufficient power to detect a good neurological outcome at hospital discharge or at one month post-injury using a dichotomized GOS good or moderate recovery versus severe disability with the expectation of 50 with good outcome in the placebo group based on the findings of Levin et al However this study should allow us to perceive trends in the data as well as determine the range and prevalence of outcomes that we might anticipate for a multi-center study of this therapy This will allow us to refine our future power calculations appropriately
Initially there will be a dose escalation component within the progesterone group but the differences in the level of circulating progesterone between the subgroups will be minimal compared to the control group Hence all progesterone treated patients are assumed to respond similarly to the treatment 2 At the completion of the pilot phase at least 100 patients will be randomized into this study GMHs trauma registry indicates that at least 145 potentially eligible TBI patients age 18 GCS 4-12 blunt mechanism and 11 hours from injury will come to GMH during the study interval Every effort will be made to obtain informed consent from a proxy in order to administer the study drug within the specified time limit 2 hours
Proposed safety and efficacy monitoring boundaries
Data Safety and Monitoring Board DSMB In accordance with standard procedures for NIH sponsored clinical trials the DSMB chair and members have been selected by the NIH-NINDS This committee will be informed of each subjects group assignment A versus B but will be blinded with respect to which group received the study drug
This committee will have three responsibilities 1 monitor identification enrollment and randomization procedures to detect any evidence of bias 2 monitor adverse events to determine if they occur disproportionately in one group and 3 monitor key clinical outcomes to determine if one group does significantly better than the other To assist the DSMB in its work our statistician Vicki Hertzberg will monitor the progress of the study on a monthly basis The DSMB will have no role in the day-to-day conduct of the trial The study statistician will report to the DSMB at quarterly meetings
Safety Monitoring A study nurse andor the research program coordinator will round on subjects daily to track their clinical progress and the occurrence of any serious adverse events SAE or adverse events AE All SAEs will be reported to the IRB DSMB and FDA within 24 hours All other adverse events will be reported to the PI IRB and FDA on a weekly basis Specific events potentially related to the study drug based on prior knowledge of the pharmacology of progesterone combination agents that include progesterone and the Intralipid carrier will be closely monitored by the study team These events include a phlebitis at the injection site b sedation unexplained by administration of other CNS medications c an increase in liver enzymes d unexplained hyperglycemia e hypotension or hypertension not known to be associated with increased intracranial pressure f unexplained fever g thromboembolic disease and h sepsis Baseline metabolic parameters will be determined from the initial blood draw prior to study drug administration Blood sampling will be performed at least once per day during drug administration for monitoring In addition hourly vital sign measurements and other parameters will be obtained from ICU charting forms Patients will be examined daily by team members for any signs of adverse reactions Team members will also review charting laboratory reports and treating physician notes daily In addition all trauma deaths are reviewed by an interdisciplinary Trauma Outcome Review Committee TORC to determine if the death was non-preventable potentially preventable or preventable A member of our study team will attend all of these meetings Ifwhen TORC reviews a death involving a participant in the study their findings will be shared with the DSMB as well as the PI and co-PI The DSMB will closely monitor the incidence of death and other serious adverse events such as sepsis or thromboembolic disease If they have concerns about the incidence of any of these events as linked to the study drug they will immediately report these concerns to the National Institute for Neurological Disorders and Stroke NINDS as well as to the Emory IRB Furthermore all occurrences of death regardless of cause and unexpected serious adverse events will be reported to the Food and Drug Administration FDA
Efficacy To assess the efficacy of the drug on an interim basis there will be a comparison of the study groups with respect to the endpoints mortality duration of coma ICP-TIL and neurological status indicators at one month at the time when 12 24 and 48 patients have been entered into the trial Comparisons at these interim points which exceed a z-score of 2782 associated p-value of 00054 will be considered significant using the OBrien-Fleming procedure
To determine if one treatment group does better than the other the teams study nurses will obtain the following outcome measures 1 ICP-TIL 2 duration of coma 3 in-hospital mortality 4 Glasgow Outcome Score 5 Disability Rating Scale and 6 Galveston Orientation and Amnesia Test The DSMB will monitor these outcomes by treatment group A versus B in order to promptly identify any between-group differences If significant differences are noted the code will be broken and our findings will be immediately reported to the Emory IRB the FDA the NINDS and DSMB
Patient accrual plan
We will enroll the first 100 eligible patients over a two year enrollment period
Ethical and consent considerations
Since our study involves treatment of patients with acute neurological impairment they are not competent to give informed consent We will therefore seek proxy consent from the patients family or next-of-kin or legally authorized representative LAR If an LAR is subsequently located that objects to the study the process will be halted and the patients participation will be terminated Only the IOCs or the study coordinator will be permitted to approach family members to request consent
A written form that complies with the polices and procedures of Emory Universitys IRB has been developed and approved This form includes the following elements title of the protocol the name of the PI study objectives and purpose a detailed description of the procedure and interventions explanation of the responsibilities of the subject and of the family members who act as proxy respondents during follow-up interviews any and all foreseeable risks anticipated benefits available alternatives an explicit statement of confidentiality non-compensation for participation the right to withdraw at any time a signature section and a number to contact the PI or a member of the study team with any questions
Given the sudden unanticipated nature of traumatic brain injury and the potential time delays involved in getting a family member to the hospital we have been authorized by the IRB to obtain proxy consent for participation over the telephone When this is necessary the on-call investigator will contact the family member provide a brief explanation of the situation read the consent form verbatim and request verbal consent over the telephone A third party will listen in to confirm that the family member understands and has provided proxy consent On the signature line of the form the witness will print the name of the consenting proxy write their own name immediately below this name note the time and date of the telephone call and check a box labeled telephone consent
Before recruiting the first patient in this study we will undertake a comprehensive process to notify and consult the target communities that use GMH as their trauma center The Emory University News and Information office has pledged its support On the advice of Emory Healthcare marketing we have allocated 40000 to support marketing and community outreach activity during the first 6 months of the study Lesser amounts have been allocated to keep the community informed in years 2 and 3 An independent interdisciplinary Safety Committee has been created to provide additional monitoring for study safety
In addition to designating a Safety Committee we will convene an independent citizen advisory committee Two influential Atlantans have agreed to co-chair this group One is Rev Gerald Durley Pastor of Providence Missionary Baptist Church one of Atlantas largest African-American congregations Rev Durley is also a key member of Concerned Black Clergy a local activist group The other co-chair is Sandy Teepen a TBI survivor safety advocate and wife of a national newspaper columnist and former editorial page editor for the Atlanta Constitution the largest circulation newspaper in the Southeastern United States
Progesterone has been used for many years to treat a variety of medical conditions Side effects ascribed to its use alone are minimal Minor adverse reactions include temperature elevations of 1 degree Fahrenheit mood changes depression following drug withdrawal vaginal cervical and uterine lining changes irregular vaginal bleeding or amenorrhea hyperventilation mild fluid retention a transient increase in low density lipoprotein LDL a transient decrease in high density lipoprotein HDL interference with lactation during breast feeding nausea abdominal cramping dizziness headaches breast pain and a delay in fertility Most of these effects are associated with prolonged administration of progesterone ie weeks to months They are unlikely to be experienced during short-course administration ie 3 days
Throughout the pilot trial subjects will be monitored for potential side effects of drug therapy ie hyperglycemia hypertension unexplained by increases in ICP unexplained fever local phlebitis thromboembolic disease abnormal vaginal bleeding The Safety Committee will meet quarterly to review group-specific clinical outcomes and side effects If they are concerned that one group is doing significantly better or worse than the other they have the authority to break the code and order premature termination of the trial
Participating pharmaceutical or device manufacturing company None
Proposed sponsor or funding agencies NINDS NIH
Significance of the Research and Impact on Medical Care If the therapeutic benefits observed in animals are replicated in humans administration of intravenous progesterone should produce several benefits including a reduction of intracerebral pressure b decreased duration of coma c decreased mortality and d improved neurological function at one month post-injury If these findings are verified it will represent a major advance in the treatment of traumatic brain injury
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 1R01NS039097-01A1 | NIH | None | httpsreporternihgovquickSearch1R01NS039097-01A1 |